Schuld, Julia and Orfanos, Zacharias and Chevessier, Frédéric and Eggers, Britta and Heil, Lorena and Uszkoreit, Julian and Unger, Andreas and Kirfel, Gregor and van der Ven, Peter F. M. and Marcus, Katrin and Linke, Wolfgang A. and Clemen, Christoph S. and Schröder, Rolf and Fürst, Dieter (2020) Homozygous expression of the myofibrillar myopathy-associated p.W2710X filamin C variant reveals major pathomechanisms of sarcomeric lesion formation. Acta Neuropathologica Communications, 8 (1), p. 154. BioMed Central. doi: 10.1186/s40478-020-01001-9. ISSN 2051-5960.
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Official URL: https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-020-01001-9
Abstract
Filamin C (FLNc) is mainly expressed in striated muscle cells where it localizes to Z-discs, myotendinous junctions and intercalated discs. Recent studies have revealed numerous mutations in the FLNC gene causing familial and sporadic myopathies and cardiomyopathies with marked clinical variability. The most frequent myopathic mutation, p.W2710X, which is associated with myofibrillar myopathy, deletes the carboxy-terminal 16 amino acids from FLNc and abolishes the dimerization property of Ig-like domain 24. We previously characterized “knock-in” mice heterozygous for this mutation (p.W2711X), and have now investigated homozygous mice using protein and mRNA expression analyses, mass spectrometry, and extensive immunolocalization and ultrastructural studies. Although the latter mice display a relatively mild myopathy under normal conditions, our analyses identified major mechanisms causing the pathophysiology of this disease: in comparison to wildtype animals (i) the expression level of FLNc protein is drastically reduced; (ii) mutant FLNc is relocalized from Z-discs to particularly mechanically strained parts of muscle cells, i.e. myotendinous junctions and myofibrillar lesions; (iii) the number of lesions is greatly increased and these lesions lack Bcl2-associated athanogene 3 (BAG3) protein; (iv) the expression of heat shock protein beta-7 (HSPB7) is almost completely abolished. These findings indicate grave disturbances of BAG3-dependent and -independent autophagy pathways that are required for efficient lesion repair. In addition, our studies reveal general mechanisms of lesion formation and demonstrate that defective FLNc dimerization via its carboxy-terminal domain does not disturb assembly and basic function of myofibrils. An alternative, more amino-terminally located dimerization site might compensate for that loss. Since filamins function as stress sensors, our data further substantiate that FLNc is important for mechanosensing in the context of Z-disc stabilization and maintenance.
Item URL in elib: | https://elib.dlr.de/135969/ | |||||||||||||||||||||||||||||||||||||||||||||
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Document Type: | Article | |||||||||||||||||||||||||||||||||||||||||||||
Title: | Homozygous expression of the myofibrillar myopathy-associated p.W2710X filamin C variant reveals major pathomechanisms of sarcomeric lesion formation | |||||||||||||||||||||||||||||||||||||||||||||
Authors: |
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Date: | 4 September 2020 | |||||||||||||||||||||||||||||||||||||||||||||
Journal or Publication Title: | Acta Neuropathologica Communications | |||||||||||||||||||||||||||||||||||||||||||||
Refereed publication: | Yes | |||||||||||||||||||||||||||||||||||||||||||||
Open Access: | Yes | |||||||||||||||||||||||||||||||||||||||||||||
Gold Open Access: | Yes | |||||||||||||||||||||||||||||||||||||||||||||
In SCOPUS: | Yes | |||||||||||||||||||||||||||||||||||||||||||||
In ISI Web of Science: | Yes | |||||||||||||||||||||||||||||||||||||||||||||
Volume: | 8 | |||||||||||||||||||||||||||||||||||||||||||||
DOI: | 10.1186/s40478-020-01001-9 | |||||||||||||||||||||||||||||||||||||||||||||
Page Range: | p. 154 | |||||||||||||||||||||||||||||||||||||||||||||
Publisher: | BioMed Central | |||||||||||||||||||||||||||||||||||||||||||||
ISSN: | 2051-5960 | |||||||||||||||||||||||||||||||||||||||||||||
Status: | Published | |||||||||||||||||||||||||||||||||||||||||||||
Keywords: | Myofibrillar myopathy, Mouse model, Filamin, Myofibrillar lesions, Muscle damage, BAG3, HSPB7, Pathophysiology, Autophagy | |||||||||||||||||||||||||||||||||||||||||||||
HGF - Research field: | Aeronautics, Space and Transport | |||||||||||||||||||||||||||||||||||||||||||||
HGF - Program: | Space | |||||||||||||||||||||||||||||||||||||||||||||
HGF - Program Themes: | Research under Space Conditions | |||||||||||||||||||||||||||||||||||||||||||||
DLR - Research area: | Raumfahrt | |||||||||||||||||||||||||||||||||||||||||||||
DLR - Program: | R FR - Research under Space Conditions | |||||||||||||||||||||||||||||||||||||||||||||
DLR - Research theme (Project): | R - Vorhaben Systemphysiologie (old) | |||||||||||||||||||||||||||||||||||||||||||||
Location: | Köln-Porz | |||||||||||||||||||||||||||||||||||||||||||||
Institutes and Institutions: | Institute of Aerospace Medicine > Muscle and Bone Metabolism | |||||||||||||||||||||||||||||||||||||||||||||
Deposited By: | Arndt, Carina | |||||||||||||||||||||||||||||||||||||||||||||
Deposited On: | 08 Sep 2020 13:19 | |||||||||||||||||||||||||||||||||||||||||||||
Last Modified: | 30 Sep 2020 10:31 |
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